Regalla Kumarswamy1, Ingo Volkmann2, Julia Beermann2, Lars Christian Napp3, Olga Jabs3, Raj Bhayadia4, Anette Melk4, Ahmet Ucar5, Kamal Chowdhury6, Johan M Lorenzen7, Shashi Kumar Gupta2, Sandor Batkai7, Thomas Thum8. 1. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany thum.thomas@mh-hannover.de regalla.kumarswamy@mh-hannover.de. 2. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany. 3. Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany. 4. Department of Kidney, Liver and Metabolic Diseases, Children's Hospital, Hannover Medical School, Hannover, Germany. 5. Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany Division of Developmental Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. 6. Department of Molecular Cell Biology, Max Planck Institute of Biophysical Chemistry, Göttingen, Germany. 7. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany. 8. Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Carl-Neuberg-Str. 1, Hannover 30625, Germany Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany National Heart and Lung Institute, Imperial College London, London, UK REBIRTH Excellence Cluster, Hannover Medical School, Hannover, Germany thum.thomas@mh-hannover.de regalla.kumarswamy@mh-hannover.de.
Abstract
RATIONALE: Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions. AIM: The objective of this study is to identify endothelial functions of the pro-hypertrophic miR-212/132 cluster and its cross-talk with other microRNAs during development and disease. METHODS AND RESULTS: We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo, deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice. CONCLUSION: Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence. Published on behalf of the European Society of Cardiology. All rights reserved.
RATIONALE: Many processes in endothelial cells including angiogenic responses are regulated by microRNAs. However, there is limited information available about their complex cross-talk in regulating certain endothelial functions. AIM: The objective of this study is to identify endothelial functions of the pro-hypertrophicmiR-212/132 cluster and its cross-talk with other microRNAs during development and disease. METHODS AND RESULTS: We here show that anti-angiogenic stimulation by transforming growth factor-beta activates the microRNA-212/132 cluster by derepression of their transcriptional co-activator cAMP response element-binding protein (CREB)-binding protein (CBP) which is a novel target of a previously identified pro-angiogenic miRNA miR-30a-3p in endothelial cells. Surprisingly, despite having the same seed-sequence, miR-212 and miR-132 exerted differential effects on endothelial transcriptome regulation and cellular functions with stronger endothelial inhibitory effects caused by miR-212. These differences could be attributed to additional auxiliary binding of miR-212 to its targets. In vivo, deletion of the miR-212/132 cluster increased endothelial vasodilatory function, improved angiogenic responses during postnatal development and in adult mice. CONCLUSION: Our results identify (i) a novel miRNA-cross-talk involving miR-30a-3p and miR-212, which led to suppression of important endothelial genes such as GAB1 and SIRT1 finally culminating in impaired endothelial function; and (ii) microRNAs may have different biological roles despite having the same seed sequence. Published on behalf of the European Society of Cardiology. All rights reserved.
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